The overall objective of this project is to determine the mechanism by which arsenic increases human health risk in people exposed to excess drinking water arsenic. Epidemiology studies of exposed populations have demonstrated a substantially increased risk of several different cancers, type 2 diabetes, vascular disease, cardiovascular disease, and reproductive and developmental problems. However, the mechanism(s) underlying these various health effects is unknown. Our laboratory previously demonstrated that arsenic is a potent endocrine disrupter, altering gene regulation by steroid receptors and several other nuclear receptors at very low, environmentally relevant doses. These effects occur through a mechanism very different than that of other known organic endocrine disrupters. We hypothesize that the ability of arsenic to disrupt nuclear receptor signaling - particularly hormone signaling - is one of the principal mechanisms by which it is able to influence the plethora of patho-physiological processes and disease states to which it has been linked. The specific goal of this research is to further investigate this hypothesis both at the mechanistic level and at the genomic and proteomic level in model cell culture and whole animal systems. Our Specific Aims are as follows: 1. Examine the mechanistic basis for disruption of steroid receptor-mediated gene transcription in model cell culture systems; 2. Determine in cell culture models the biological consequences of arsenic alterations in steroid receptor signaling using toxico-genomic and -proteomic approaches; 3. Determine in whole animal models the biological consequences of arsenic alterations in steroid receptor signaling using genomic and proteomic approaches. In addition to these primary aims, we propose several Sub-Aims that involve collaborations with other Projects within this program and with another SBRP Program, principally focusing on a comparison of the toxicogenpmics of arsenic in these biological systems. The goals of this study are to provide mechanistic insight into the basis of the endocrine disrupting effects of arsenic, to determine the biological consequences of such effects, and to identify potential biomarkers of exposure or effects that are useful in assessing the overall impact of arsenic exoosure on human health.